Diabetes generally refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Patients with Type 2 diabetes mellitus have an increased risk of macrovasuclar and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are important in the clinical management and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes, Type I and II. In Type I diabetes (also known as insulin-dependent diabetes mellitus (IDDM)) patients produce little or no insulin, the hormone which regulates glucose utilization. In Type II diabetes (also known as non-insulin dependent diabetes mellitus (NIDDM)) patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance. Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
The available treatments for Type II diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic β-cells to secrete more insulin, and/or by injection of insulin when sulphonylureas or meglitinide become-ineffective, can result in insulin concentrations high enough to stimulate insulin-resistance tissues. However dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. Biguanides can increase insulin sensitivity resulting in some correction of hyperglycemia. However, two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea. Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type II diabetes.
Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a more recently described class of compounds with potential for ameliorating many symptoms of Type II diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type II diabetes resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR), primarily the PPAR-gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type II diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from glitazones (i.e., they are not thiazolidinediones). Serious side effects (e.g. liver toxicity) have occurred with some PPAR agonists, such as troglitazone.
Other treatments are under investigation, including treatment with alpha-glucosidase inhibitors (e.g., acrabose) and protein tyrosine phosphatase-1B (PTP-1B) inhibitors.
Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DP-IV” or “DPP-IV”) enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type II diabetes. See, for example, WO 97/40832, WO 98/19998, U.S. Pat. No. 5,939,560, Bioorg. Med. Chem. Lett. 6(10):1163-1166 (1996), and Bioorg. Med. Chem. Lett. 6(22):2745-2748 (1996). The usefulness of DPP-IV inhibitors in the treatment of Type II diabetes is based on the fact that DPP-IV in vivo readily inactivates glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin. Inhibition of DPP-IV leads to decreased inactivation of the incretins, and this in turn results in increased effectiveness of the incretins in stimulating production of insulin by the pancreas. DPP-IV inhibition therefore results in an increased level of serum insulin. Advantageously, since the incretins are produced by the body only when food is consumed, DPP-IV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Inhibition of DPP-IV is therefore expected to increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secretagogues. Improved DPP-IV inhibitors are needed for better treatment of diabetes.
Shown below are DPP-IV inhibitors which have reached advanced stages of human clinical trials:

Formulas A, B, and C are Novartis NVP-DPP-728, Probiodrug P32/98, and Novartis NVP-LAF-237, respectively. Other anti-diabetic agents are described in WO 2003/084940, JMC (2003) 46(13):2774-2789, WO 03/037327, EP 1354882 A1, U.S. Pat. No. 6,011,155, WO 00/34241, and U.S. Pat. No. 6,166,063.
Japanese Patent Application Publication No. JP 2004-26820, International Patent Publication No. WO2002/0384541, and U.S. Patent Publication No. 2004/0072892 disclose cyanopyrrolidine derivatives having DPP-IV inhibition activity. According to US 2004/0072892, these compounds have the formula:
wherein:
R1 is a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms;
R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R1 and R2 together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms;
R3 and R4 are each a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms or an alkyl group having 1 to 5 carbon atoms, or R3 and R4 together form an oxo, a hydroxyimino group, an alkoxyimino group having 1 to 5 carbon atoms or an alkylidene group having 1 to 5 carbon atoms;
X is an oxygen atom or a sulfur atom;
Y is —C5R6— (wherein R5 and R6 are the same or different, and are each a hydrogen atom, a halogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms or an optionally substituted alkenyl group having 2 to 10 carbon atoms), or —CR7R8—CR9R10— (wherein R7, R8, R9 and R10 are the same or different, and each a hydrogen atom, a halogen atom or an optionally substituted alkyl group having 1 to 10 carbon atoms, or R7 and R9 together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, an optionally substituted cycloalkenyl group having 4 to 8 carbon atoms, an optionally substituted bicycloalkyl group having 5 to 10 carbon atoms, or an optionally substituted bicycloalkenyl group having 5 to 10 carbon atoms) and
Z is a hydrogen atom or an optionally substituted alkyl group having 1 to 10 carbon atoms, or Y and Z together with the nitrogen atom to which they are attached form an optionally substituted cyclic amino group having 2 to 10 carbon atoms, or a pharmaceutically acceptable salt thereof.
U.S. Patent Application Publication Nos. 2004/0121964 and 2004/0259843 disclose compounds of the formula:
where
X is CH2, CHF, or CF2,
R is alkylcarbonyl, alkylcarbonyl, cyano, heterocyclecarbonyl, R4R5NC(O)—, B(OR6)2, (1,2,3)-dioxoborolane or 4,4,5,5-tetramethyl-(1,2,3)-dioxoborolane,
R1 is alkoxyalkyl, alkyl, alkylcarbonyl, alkenyl, alkynyl, allenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkyl, haloalkenyl, heterocyclealkyl, or hydroxyalkyl,
R2 and R3 are independently hydrogen, alkoxyalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, or hydoxyalkyl; or R2 and R3 taken together with the atoms to which they are attached form a particular mono or bicyclic heterocycle, and
R4 and R5 are independently hydrogen, alkyl, or arylalkyl. According to the applications, these compounds inhibit DPP-IV and are useful for the prevention or treatment of diabetes (especially type II diabetes), hyperglycemia, Syndrome X, hyperinsulinemia, obesity, atherosclerosis, and various immunomodulatory diseases.
International Publication No. WO 2005/023762 discloses compounds of the formula
where A is a particular monocyclic or bicyclic aryl or heteroaryl group. According to the application, these compounds inhibit DPP-IV and are useful for the prevention or treatment of diabetes, hyperglycemia, syndrome X, hyperinsulinemia, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.